This invention relates to compositions comprising bis biguanide antimicrobial agents in combination with one or more anionic active ingredients. In particular, this invention relates to the employment of bis biguanide as the antimicrobial agent in an antiplaque oral composition wherein an anionic active ingredient is also employed.
The bis biguanide compounds of which this invention is concerned are described in German patent application No. P2,332,383 published on Jan. 10, 1974 and have the generic formula ##STR1## wherein A and A' each represent either (1) a phenyl radical which optionally is substituted by one alky1 or alkoxy group containing from 1 to about 4 carbon atoms, a nitro group, or a halogen atom; (2) an alkyl group containing from 1 to about 12 carbon atoms; or (3) alicyclic groups containing from 4 to about 12 carbon atoms; wherein X and X' each represent an alkylene radical containing from 1 to 3 carbon atoms; wherein Z and Z' each can be either 0 to 1; wherein R and R' each represent either hydrogen, or alkyl radical containing from 1 to about 12 carbon atoms, or an aralkyl radical containing from 7 to about 12 carbon atoms; wherein n is an integer from 2 to 12 inclusive; and wherein the chain (CH.sub.2).sub.n may optionally be interrupted by oxygen or sulfur atoms, aromatic nuclei, etc.
These compounds have long been known to have antimicrobial properties, and in particular have been known to be useful in oral compositions as antimicrobial antiplaque agents. The employment of these compounds in commercial products has been severely hampered by virtue of at least two properties of the bis biguanides: to wit, they are highly cationic and are known to stain dental surface.
The cationic nature of these compounds has greatly inhibited their use. This, for example, in British Patent 825,5777 published Dec. 16, 1959 it is described that these highly cationic antimicrobials, when incorporating in conventional dentifrice compositions were not effectively absorbed onto dental surfaces whereas mere aqueous compositions containing the antimicrobial were effective. The British patent then discloses that the culprit in reducing the affectivity of these cationic bis-biguanide antimicrobials was the presence in such dental compositions of anionic detergents such as sodium lauryl sulphate, sodium lauryl sarcosinate and soap. These surfactants have traditionally been incorporated into oral compositions to provide the composition with foaming properties. Taught, therefore, in this British Patent is the use of non-anionic surfactants, e.g. cationic, non-ionic or anpholytic detergents. By avoiding the use of anionic detergents, the inactivation of the cationic bis biguidine is said to have been avoided.
Unfortunately, the simple solution of avoiding anionic surfactants is not applicable to the problem faced by modern formulators who wish to employ the cationic bis biguanides in oral compositions. While an abundance of non-anionic surfactants are now available, it is also desirable to incorporate into oral compositions a host of newly developed or newly employed compounds for therapeutic, prophylactic, aesthetic or organoleptic purposes and many of these compounds are anionic in such compositions. Thus, for example, modern oral compositions contain anti-tartar e.g. phosphoric compounds which are highly anionic; anticaries agents such as fluorides which are highly anionic; antistaining agents to counteract the staining properties of the cationic antimicrobial agents, which antistaining agents are likewise anionic; and the like. Not surprisingly, these anionic agents tend to associate with the cationic antimicrobials and in the extreme, precipitate out of solution, thereby rendering either the antimicrobial or the anionic agent ineffective. Accordingly, in many cases, the formulator has been forced to seek substitutes for the otherwise highly effective bis-biguanides.
This problem has been raised, for example, in the specification of U.S. Pat. No. 3,934,002 issued to John Wilkins Haefele on Jun. 20, 1976 and incorporated herein by reference. The specification is directed toward providing an oral composition for plaque, caries and calculus retardation with reduced staining tendencies. The bis-biguanides are described as useful and the problem, already recognized by the above cited British Patent, is acknowledged by Haefele. Consequently, Haefele teaches that a suitable sudsing agent will be one that will not react with the bis-biguanide compound, i.e. a non-soap nonionic, cationic, zwitterionic or amphoteric detergent will be suitable.
In accordance with Haefele, the bis-biguanides are combined with one or more of a long list of anticalculus agents including, for example, ammonium chlorides, water soluble salts of polycarboxylic acids, and polyphosphonates, all of which are, to varying degrees, anionic. Recognizing the possibility of association between the anionic anti-calculus agent and the cationic bis biguanide, Haefele teaches that when the bis biguanide selected is more soluble than the salt resulting from the association of bis biguanide with the anticalculus agent, then an excess of the anticalculus agent must be used or otherwise, the two will react leaving insufficient free anticalculus agent. Unfortunately, while it may be theoretically possible to add sufficient anticalculus agent in this manner so as to ensure an effective amount of such anticalculus agent unassociated with the cationic antimicrobial, the laws of chemical equilibrium being what they are, such excess anticalculus agent will deplete the composition of antimicrobial agent. In fact, when considering the problem generally, it will be recognized that because of the constraints imposed by equilibrium and mass action criteria, the degrees of freedom existing in such a system are insufficient to allow a formulation to combine the cationic antimicrobial with an anionic agent and arbitrarily select the effective concentration of both in the composition. Instead, one such concentrate may be selected and the laws of the system will dictate the other.
Accordingly, heretofore there has been no satisfactory method of insuring effective concentrations of both anionic agents and the cationic bis biguanide, therefor greatly limiting the wide use of these otherwise highly effective antimicrobial agents.